EP0819764B1 - Use of o-beta-d-galactopyranosyl-d-xyloses for the preparation of compositions and solutions intended to the evaluation of intestinal lactase, and production process - Google Patents

Use of o-beta-d-galactopyranosyl-d-xyloses for the preparation of compositions and solutions intended to the evaluation of intestinal lactase, and production process Download PDF

Info

Publication number: EP0819764B1
Authority: EP; European Patent Office
Prior art keywords: xylose; galactopyranosyl; disaccharides; process according; beta
Prior art date: 1995-11-08
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

EP96937342A

Other languages

German (de)

English (en)

French (fr)

Other versions

EP0819764A1 (en

Inventor

Juan José Aragon Reyes

Francisco Javier Canada Vicinay

Alfonso Fernandez-Mayoralas Alvarez

Rosa Lopez Alvarez

Manuel Martin Lomas

Daniel Villanueva Torregroza

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Universidad Autonoma

Consejo Superior de Investigaciones Cientificas CSIC

Original Assignee

Universidad Autonoma

Consejo Superior de Investigaciones Cientificas CSIC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-11-08

Filing date

1996-11-08

Publication date

2002-03-20

1996-11-08 Application filed by Universidad Autonoma, Consejo Superior de Investigaciones Cientificas CSIC filed Critical Universidad Autonoma

1998-01-21 Publication of EP0819764A1 publication Critical patent/EP0819764A1/en

2002-03-20 Application granted granted Critical

2002-03-20 Publication of EP0819764B1 publication Critical patent/EP0819764B1/en

2016-11-08 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

108010005774 beta-Galactosidase Proteins 0.000 title claims abstract description 41
102100026189 Beta-galactosidase Human genes 0.000 title claims abstract description 35
108010059881 Lactase Proteins 0.000 title claims abstract description 32
229940116108 lactase Drugs 0.000 title claims abstract description 32
239000000203 mixture Substances 0.000 title claims abstract description 28
230000000968 intestinal effect Effects 0.000 title claims abstract description 22
238000011156 evaluation Methods 0.000 title claims abstract description 12
238000002360 preparation method Methods 0.000 title claims abstract description 8
238000004519 manufacturing process Methods 0.000 title claims 2
150000002016 disaccharides Chemical class 0.000 claims abstract description 56
SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims abstract description 35
238000000034 method Methods 0.000 claims abstract description 31
SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims abstract description 20
230000008569 process Effects 0.000 claims abstract description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
ZTTRCZJSZGZSTB-GDIDZOIGSA-N (2r,3s,4r)-2,4,5-trihydroxy-3-[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanal Chemical compound OC[C@@H](O)[C@@H]([C@@H](O)C=O)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O ZTTRCZJSZGZSTB-GDIDZOIGSA-N 0.000 claims abstract description 8
AXHPKHDTOXXPGU-IGXVCFLBSA-N (2r,3s,4r)-3,4,5-trihydroxy-2-[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanal Chemical compound OC[C@@H](O)[C@H](O)[C@H](C=O)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O AXHPKHDTOXXPGU-IGXVCFLBSA-N 0.000 claims abstract description 8
AXHPKHDTOXXPGU-UHFFFAOYSA-N 2-O-beta-D-galactopyranosyl-D-xylose Natural products OCC(O)C(O)C(C=O)OC1OC(CO)C(O)C(O)C1O AXHPKHDTOXXPGU-UHFFFAOYSA-N 0.000 claims abstract description 8
ZTTRCZJSZGZSTB-UHFFFAOYSA-N O3-beta-D-Galactopyranosyl-L-arabinose Natural products OCC(O)C(C(O)C=O)OC1OC(CO)C(O)C(O)C1O ZTTRCZJSZGZSTB-UHFFFAOYSA-N 0.000 claims abstract description 8
239000000758 substrate Substances 0.000 claims abstract description 8
230000015572 biosynthetic process Effects 0.000 claims abstract description 7
238000001914 filtration Methods 0.000 claims abstract description 4
238000010438 heat treatment Methods 0.000 claims abstract description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 3
239000012736 aqueous medium Substances 0.000 claims abstract description 3
238000004809 thin layer chromatography Methods 0.000 claims abstract description 3
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 14
239000008101 lactose Substances 0.000 claims description 12
BYZQBCIYLALLPA-UHFFFAOYSA-N O4-beta-D-Galactopyranosyl-D-xylose Natural products O=CC(O)C(O)C(CO)OC1OC(CO)C(O)C(O)C1O BYZQBCIYLALLPA-UHFFFAOYSA-N 0.000 claims description 9
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
VEXXNWQUANSCBT-UHFFFAOYSA-N 4-O-beta-D-Galactopyranosyl-D-xylose Natural products OC1C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O VEXXNWQUANSCBT-UHFFFAOYSA-N 0.000 claims description 5
VCTBNHVCBSUQPG-MRRNQDDQSA-N 4-o-β-d-galactopyranosyl-d-xylose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)OC1 VCTBNHVCBSUQPG-MRRNQDDQSA-N 0.000 claims description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
239000000654 additive Substances 0.000 claims description 3
230000000996 additive effect Effects 0.000 claims description 3
229910052799 carbon Inorganic materials 0.000 claims description 3
239000003795 chemical substances by application Substances 0.000 claims description 3
239000006184 cosolvent Substances 0.000 claims description 3
239000003623 enhancer Substances 0.000 claims description 3
230000001012 protector Effects 0.000 claims description 3
239000003381 stabilizer Substances 0.000 claims description 3
241000588724 Escherichia coli Species 0.000 claims description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
230000002255 enzymatic effect Effects 0.000 claims description 2
102000005936 beta-Galactosidase Human genes 0.000 claims 4
239000000243 solution Substances 0.000 claims 4
239000003755 preservative agent Substances 0.000 claims 2
WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 claims 1
239000007864 aqueous solution Substances 0.000 claims 1
239000003480 eluent Substances 0.000 claims 1
239000000499 gel Substances 0.000 claims 1
230000000694 effects Effects 0.000 description 17
210000002700 urine Anatomy 0.000 description 16
PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 15
238000006243 chemical reaction Methods 0.000 description 6
239000000047 product Substances 0.000 description 6
125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
238000001727 in vivo Methods 0.000 description 5
BYZQBCIYLALLPA-NOPGXMAYSA-N (2r,3r,4r)-2,3,5-trihydroxy-4-[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanal Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BYZQBCIYLALLPA-NOPGXMAYSA-N 0.000 description 4
241001465754 Metazoa Species 0.000 description 4
241000700159 Rattus Species 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
230000008030 elimination Effects 0.000 description 4
238000003379 elimination reaction Methods 0.000 description 4
230000000474 nursing effect Effects 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 3
239000008280 blood Substances 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
150000001875 compounds Chemical class 0.000 description 3
230000007812 deficiency Effects 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
229930182830 galactose Natural products 0.000 description 3
239000008103 glucose Substances 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
238000002955 isolation Methods 0.000 description 3
XGEJOTVKROWVLG-ITHKSCCZSA-N (2r,3s,4r)-2,3,4,5-tetrahydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]pentan-1-one Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)C(=O)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O XGEJOTVKROWVLG-ITHKSCCZSA-N 0.000 description 2
RMTFNDVZYPHUEF-XZBKPIIZSA-N 3-O-methyl-D-glucose Chemical compound O=C[C@H](O)[C@@H](OC)[C@H](O)[C@H](O)CO RMTFNDVZYPHUEF-XZBKPIIZSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
239000000370 acceptor Substances 0.000 description 2
230000009471 action Effects 0.000 description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
238000004737 colorimetric analysis Methods 0.000 description 2
230000002950 deficient Effects 0.000 description 2
238000001514 detection method Methods 0.000 description 2
239000012153 distilled water Substances 0.000 description 2
229940088598 enzyme Drugs 0.000 description 2
238000000605 extraction Methods 0.000 description 2
230000002503 metabolic effect Effects 0.000 description 2
150000002772 monosaccharides Chemical class 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
238000001228 spectrum Methods 0.000 description 2
-1 β-Gluco-Pyranosyl disaccharides Chemical class 0.000 description 2
XUGMDBJXWCFLRQ-WRWGMCAJSA-N (2r,3r,4s,5r)-2-phenylmethoxyoxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)CO[C@H]1OCC1=CC=CC=C1 XUGMDBJXWCFLRQ-WRWGMCAJSA-N 0.000 description 1
NTQWZXRSBBGWFC-YOUNRWHRSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3r,4s,5r)-2,4,5-trihydroxyoxan-3-yl]oxyoxane-3,4,5-triol Chemical class O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O)CO[C@H]1O NTQWZXRSBBGWFC-YOUNRWHRSA-N 0.000 description 1
HXOXUDVNFQMLDB-FCCWNNDSSA-N (3R,4R,5S,6R)-6-(hydroxymethyl)-2-methyl-5-[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-2,3,4-triol Chemical compound CC1(O)[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO HXOXUDVNFQMLDB-FCCWNNDSSA-N 0.000 description 1
0 *[C@]1[C@@](*)C(O)O*C1O Chemical compound *[C@]1[C@@](*)C(O)O*C1O 0.000 description 1
CWRWJDAEKWYUJT-CGKXPTHNSA-N 1-(9S,13S,12-oxophytodienoyl)-2-(7Z,10Z,13Z)-hexadecatrienoyl-3-(beta-D-galactosyl)-sn-glycerol Chemical compound C([C@H](OC(=O)CCCCC\C=C/C\C=C/C\C=C/CC)COC(=O)CCCCCCC[C@@H]1[C@@H](C(=O)C=C1)C\C=C/CC)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O CWRWJDAEKWYUJT-CGKXPTHNSA-N 0.000 description 1
206010010356 Congenital anomaly Diseases 0.000 description 1
206010012735 Diarrhoea Diseases 0.000 description 1
206010013082 Discomfort Diseases 0.000 description 1
230000005526 G1 to G0 transition Effects 0.000 description 1
241000222025 Hamamotoa singularis Species 0.000 description 1
239000007836 KH2PO4 Substances 0.000 description 1
241000124008 Mammalia Species 0.000 description 1
241001494479 Pecora Species 0.000 description 1
239000012507 Sephadex™ Substances 0.000 description 1
241000222068 Sporobolomyces <Sporidiobolaceae> Species 0.000 description 1
PHENPABYBHPABM-UHFFFAOYSA-N acetic acid;octane Chemical compound CC(O)=O.CCCCCCCC PHENPABYBHPABM-UHFFFAOYSA-N 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
230000008901 benefit Effects 0.000 description 1
XSXQXHMPBBNYRD-YHLIKCGVSA-N beta-D-Galp-(1->3)-beta-D-Xylp Chemical class O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O)OC[C@H]1O XSXQXHMPBBNYRD-YHLIKCGVSA-N 0.000 description 1
235000010290 biphenyl Nutrition 0.000 description 1
239000004305 biphenyl Substances 0.000 description 1
125000006267 biphenyl group Chemical group 0.000 description 1
229910052681 coesite Inorganic materials 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
229910052906 cristobalite Inorganic materials 0.000 description 1
238000010511 deprotection reaction Methods 0.000 description 1
238000011161 development Methods 0.000 description 1
230000029087 digestion Effects 0.000 description 1
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
210000003608 fece Anatomy 0.000 description 1
239000012467 final product Substances 0.000 description 1
235000013305 food Nutrition 0.000 description 1
125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
238000004817 gas chromatography Methods 0.000 description 1
210000001035 gastrointestinal tract Anatomy 0.000 description 1
239000011521 glass Substances 0.000 description 1
230000013595 glycosylation Effects 0.000 description 1
238000006206 glycosylation reaction Methods 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
239000001257 hydrogen Substances 0.000 description 1
229910052739 hydrogen Inorganic materials 0.000 description 1
125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
239000000543 intermediate Substances 0.000 description 1
210000000936 intestine Anatomy 0.000 description 1
229910001629 magnesium chloride Inorganic materials 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
239000008267 milk Substances 0.000 description 1
210000004080 milk Anatomy 0.000 description 1
235000013336 milk Nutrition 0.000 description 1
238000012986 modification Methods 0.000 description 1
230000004048 modification Effects 0.000 description 1
229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
238000000746 purification Methods 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
238000007790 scraping Methods 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
210000000813 small intestine Anatomy 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
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238000012360 testing method Methods 0.000 description 1
238000012546 transfer Methods 0.000 description 1
229910052905 tridymite Inorganic materials 0.000 description 1
DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1

Images

Classifications

- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/12—Disaccharides
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/924—Hydrolases (3) acting on glycosyl compounds (3.2)

Definitions

the present invention is comprised in the field of bloodless evaluation methods of intestinal lactase acitivity.
the determination of the intestinal lactase activity is of importance in paedriatrics and gastroenterology and may be directly carried out, parting from a mucous sample, or indirectly, parting from the level of glucose in the blood or from the expired hydrogen, after the administration of a dose to the individual.
the indirect determination has the advantage of being a technique involving blood, which requires the extraction of blood by a specialied person before the sample may be analyzed, apart from being complex and susceptible to errors, due to the existance of glucose originating from the digestion of other food taken by the individual, and of endogenous glucose which might have been mobilized.
Spanish Patent ES-P-9001680 discloses the preparation of disaccharide 4-O- ⁇ -galactopyranosyl-D-xylose of formula (I) for the evaluation of the intestinal lactase activity.
Said disaccharide is administrated orally, it acts as substrate of the intestinal lactase and decomposes, in the intestinal tract, in xylose and galactose, the xylose being absorbed and then eliminated with urine where it may be directly evaluated by means of a simple colorimetric method.
Spanish Patent ES-P-9001680 also discloses a method of preparation for the 4-O- ⁇ -galactopyranosyl-D-xylose, which basically comprises a synthesis parting from benzyl- ⁇ -D-xylopyranoside and which follows operational sequences which imply selective protection reactions, glycosylation and deprotection. Both the number of reaction stages, the use of expensive reactive agents such as silver triflate in the glyxosylation reaction, and the employment of chromatographic columns in the purification of intermediates and the final product, produce costs and present difficulties for the performance of said procedure at industrial scale.
the object of the present invention is the use of ⁇ -D-galactopyranosyl-D-xyloses, specifically of 4-O- ⁇ -D-galactopyranosyl-D-xylose together with 2-O- ⁇ -D-galactopyranosyl-D-xylose of the general formula (II) and of 3-O- ⁇ -D-galactopyranosyl-D-xylose, of the 35 general formula (III) for the preparation of compositions and solutions used for the bloodless and reliable evaluation of intestinal lactase.
another object of the invention is a process which permits the preparation of the ⁇ -D-galactopyranosyl-D-xyloses, the use of which is claimed, together with that of other ⁇ -D-galactopyranosyl-D-xyloses, by means of a simplified method versus the conventional procedures of this type of disaccharides.
the ⁇ -D-galactopyranosyl-D-xyloses that is to say, the 2-O- ⁇ -D-galactopyranosyl-D-xylose and the 3-O- ⁇ -D-galactopyranosyl-D-xylose the use of which is claimed, present an affinity to the lactase which is substantially enhanced versus the conventionally used disaccharides in this type of evaluations, which results to be surprising in view of the fact that both compounds are structurally less similar to lactose than the previously used compounds, such as the 4-O- ⁇ -galactopyranosyl-D-xylose, from which they are structurally differentiated by various hydroxyl groups respectively adjacent to the glycosydic bond in the molecule.
compositions and solutions which are conventional in themselves, individually or jointly, and mixed with a quantity of conventional dissaccharide of formula (I), and with lower quantities of lactose.
Such compositions and solutions may contain quantities of ingredients conventional in themselves, pharmaceutically acceptable, of at least one selected additive from among stabilizers, protectors, taste enhancers, lactose, gelifiants, fluxants and conservatives.
the solutions may be water, aqueous or saline solutions which are conventional in themselves.
the process according to the invention includes the possibility of preparing ⁇ -D-galactopyranosyl-D-xylose which include the previously indicated disaccharides I, II and III, and comprises the following stages: React a D-xylose and a substrate of ⁇ -D-galactopyranoside in the presence of a ⁇ -galactosidase enzyme, according the drawing of the reaction the concentration of D-xylose being from 2 to 20 times over that of the ⁇ -D-galactopyranoside, in an aqueous medium buffered to a pH of 5,0 - 9,0 and at a temperature comprised between 4 and 37oC; deactivate the ⁇ -galactosydose, by heating at 100oC when reaching the maximum yield of formation of disaccharides detected (normally after 4 to 8 hours) by means of thin layer chromatography or with an active carbon column, and isolation of the formed disaccharides through filtration in a packed column with a thinner selected between water or water/alco
the ⁇ -D-galactopyranoside used is O-nitrophenyl, ⁇ -D-galactopyranoside while in another embodiment it is lactose.
the ⁇ -galactosidase may be for example, the Escherichia Coli, as commercialized by Spanish Company SIGMA-ALDRICH QU ⁇ MICA, S.A.
the process may be conducted in the presence of cosolvents miscible in water, such as acetonitrile, dimethyl formamide or dimethyl sulfoxide.
cosolvents miscible in water such as acetonitrile, dimethyl formamide or dimethyl sulfoxide.
the filtration columns employed for the isolation of the disaccharides may be packed with SephadexTM G-10 or BiogelTM P2, or else with active carbon.
Disaccharides II and III may as such also be obtained through other conventional methods, such as those disclosed by Gorin et al. in "The Synthesis of ⁇ -Galacto And ⁇ -Gluco-Pyranosyl disaccharides by Sporobolomyces Singilaris ", Can. J. Chem. 42(1964) 2307-2319.
the single figure is a graphic representation of the evolution of a) the hydrolysis in vivo, of a mixture of the ⁇ -D-galactopyranosyl-D-xylose (I), (II) and (III) as a percentage of xylose eliminated through urine and b) the intestinal lactase activity (nm/min/mg protein) during the growth of rats as described in the examples
Example 1 Preparation of a mixture of 4-O- ⁇ -D-galactopyranosyl-D-xylose (disaccharide I), 2-O- ⁇ -D-galactopyranosyl-D-xylose (disaccharide II) and 3-O- ⁇ -D-galactopyranosyl-D-xylose (disaccharide III).
disaccharides I, II and III comprise, some were separated, with each one of them pure, which were used to characterize them by RNM.
the 'H-RMN spectrum 300 MHz, D 2 O), measured with a Varian XL-300 spectometer, of the fractions with disaccharide I, was identical to that of the previously prepared product.
the ratio of disaccharides I, II and III obtained in the chromatographic column was determined by gas chromatography with a chromatograph equipped with a flame ionization detector and capilar column SE-54 (stationary phase: 5% diphenyl and 95% dimethyl polysyloxane, 15 m length, 0,15 mm inside diameter, and ⁇ m thickness). In the analysis, a nitrogen flow of 1mL/min was used. The temperature programmes used were: initial temperature 160°C; initial time 2 min; temperature increase 5°C/min; final temperature: 250°C.
Disaccharides I, II and III and lactose were hydrolized according to the method of A.Rivera-Sagredo, F.J.Canada, O.Nieto, J.Jiménez-Barbero and M.Martin-Lomas, Eur. J.Biochem., 209 (1992) 415-422, with intestinal lactase of a sheep at pH 6.0, with the following results, in relation to constants of Michaelis (K m ) and maximum rates (V max. ): Disaccharide K m (mM) V max (%) lactose 11,0 100 disaccharide I 340,0 20 disaccharide II 14,0 20 disaccharide III 4,0 70
Example 3 Elimination of xylose in urine after oral administration of a mixture of disaccharides I, II and III
Example 4 A group of Sprague-Dawley nursing rats of the same litter and with 15 days of age, were kept without eating during four hours in metabolical boxes at 30°C. Each one of them was administered 18.2g of disaccharide I in 0.5 ml of distilled water. Urine was collected from the animals, pressing the bladder transabdominally during 5 hours. The xylose eliminated through the urine during this time was evaluated spectroscopically. The elimination of xylose resulted to be of 21%, that is to say, less than half than the result of the mixture of products I, II and III after 15 days.

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EP96937342A 1995-11-08 1996-11-08 Use of o-beta-d-galactopyranosyl-d-xyloses for the preparation of compositions and solutions intended to the evaluation of intestinal lactase, and production process Expired - Lifetime EP0819764B1 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
ES9502185		1995-11-08
ES09502185A ES2100131B1 (es)	1995-11-08	1995-11-08	Procedimiento enzimatico de obtencion de beta-d-galactopiranosil-d-xilosas utilizables para la evaluacion diagnostica de la lactasa intestinal.
PCT/ES1996/000208 WO1997017464A1 (es)	1995-11-08	1996-11-08	USO DE β-D-GALACTOPIRANOSIL-D-XILOSAS PARA LA PREPARACION DE COMPOSICIONES Y DISOLUCIONES DESTINADAS A LA EVALUACION DE LA LACTASA INTESTINAL, Y PROCEDIMIENTO PARA SU OBTENCION

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EP0819764A1 EP0819764A1 (en)	1998-01-21
EP0819764B1 true EP0819764B1 (en)	2002-03-20

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EP96937342A Expired - Lifetime EP0819764B1 (en)	1995-11-08	1996-11-08	Use of o-beta-d-galactopyranosyl-d-xyloses for the preparation of compositions and solutions intended to the evaluation of intestinal lactase, and production process

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US (1)	US5994092A (cs)
EP (1)	EP0819764B1 (cs)
JP (2)	JP3036848B2 (cs)
KR (1)	KR19980701287A (cs)
CN (1)	CN1220779C (cs)
AT (1)	ATE214740T1 (cs)
AU (1)	AU702329B2 (cs)
BR (1)	BR9607092A (cs)
CA (1)	CA2209927C (cs)
CZ (1)	CZ252797A3 (cs)
DE (1)	DE69619973T2 (cs)
EA (1)	EA000684B1 (cs)
ES (2)	ES2100131B1 (cs)
HU (1)	HUP9801439A3 (cs)
NO (1)	NO973159L (cs)
NZ (1)	NZ321607A (cs)
PL (1)	PL321257A1 (cs)
PT (1)	PT819764E (cs)
SK (1)	SK100197A3 (cs)
WO (1)	WO1997017464A1 (cs)

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ES2130073B1 (es) *	1997-05-28	2000-04-01	Consejo Superior Investigacion	Mejoras en el procedimiento de obtencion de beta-d-galactopiranosil-xilosas utilizables para la evaluacion diagnostica de la lactasa intestinal.
JP3017151B2 (ja)	1997-11-26	2000-03-06	静岡日本電気株式会社	携帯装置のハンドストラップとこのハンドストラップの取付構造
ES2182703B1 (es) *	2001-06-18	2004-06-01	Consejo Superior De Investigaciones Cientificas	Un procedimiento enzimatico para obtener 4-0-b-d-galactopiranosil-d-xilosa, 4-o-b-d-galactopiranosil-d-xilosa obtenida de acuerdo con el pr cedimiento, composiciones que la contienen y su uso en la evaluacion de la lactasa intestinal.
ES2208099B1 (es) *	2002-10-16	2005-09-01	Consejo Sup. De Invest. Cientificas	Empleo de 4-galactosil-xilosa en humanos para la evaluacion in vivo de lactasa intestinal como prueba diagnostica no invasiva de la deficiencia de este enzima.
JP2006223268A (ja) *	2005-02-21	2006-08-31	Yakult Honsha Co Ltd	ガラクトシル２糖類の製造法
US20110196219A1 (en) *	2010-02-08	2011-08-11	Edmunds Kathleen	Fetal Scalp Blood Analyzer
US20110196214A1 (en) *	2010-02-08	2011-08-11	Edmunds Kathleen	Fetal Scalp Blood Analyzer
US9128100B2 (en)	2011-01-14	2015-09-08	Venter Pharma, S.L.	Non-invasive diagnostic method for the evaluation of intestinal lactase deficiency (hypolactasia)
WO2018100120A1 (en)	2016-11-30	2018-06-07	Elaphe Pogonske Tehnologije D.O.O.	Electric machine with a cooling system and a method for cooling an electric machine

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ES2023556A6 (es) *	1990-06-18	1992-01-16	Consejo Superior Investigacion	Procedimiento de obtencion de 4-o-beta-d-galactopiranosil-d-xilosa utilizable para la evaluacion diagnostica de la lactasa intestinal.
JP2834871B2 (ja) *	1990-08-07	1998-12-14	塩水港精糖株式会社	フラクトース含有オリゴ糖の製造法

1995
- 1995-11-08 ES ES09502185A patent/ES2100131B1/es not_active Expired - Fee Related
1996
- 1996-11-08 KR KR1019970704676A patent/KR19980701287A/ko not_active Ceased
- 1996-11-08 SK SK1001-97A patent/SK100197A3/sk unknown
- 1996-11-08 EA EA199700097A patent/EA000684B1/ru not_active IP Right Cessation
- 1996-11-08 NZ NZ321607A patent/NZ321607A/xx unknown
- 1996-11-08 HU HU9801439A patent/HUP9801439A3/hu unknown
- 1996-11-08 PT PT96937342T patent/PT819764E/pt unknown
- 1996-11-08 US US08/875,043 patent/US5994092A/en not_active Expired - Lifetime
- 1996-11-08 PL PL96321257A patent/PL321257A1/xx unknown
- 1996-11-08 CN CNB961923989A patent/CN1220779C/zh not_active Expired - Fee Related
- 1996-11-08 AT AT96937342T patent/ATE214740T1/de not_active IP Right Cessation
- 1996-11-08 DE DE69619973T patent/DE69619973T2/de not_active Expired - Lifetime
- 1996-11-08 JP JP09517877A patent/JP3036848B2/ja not_active Expired - Fee Related
- 1996-11-08 AU AU74977/96A patent/AU702329B2/en not_active Ceased
- 1996-11-08 BR BR9607092A patent/BR9607092A/pt not_active Application Discontinuation
- 1996-11-08 WO PCT/ES1996/000208 patent/WO1997017464A1/es not_active Ceased
- 1996-11-08 ES ES96937342T patent/ES2176505T3/es not_active Expired - Lifetime
- 1996-11-08 CA CA002209927A patent/CA2209927C/en not_active Expired - Fee Related
- 1996-11-08 EP EP96937342A patent/EP0819764B1/en not_active Expired - Lifetime
- 1996-11-08 CZ CZ972527A patent/CZ252797A3/cs unknown
1997
- 1997-07-08 NO NO973159A patent/NO973159L/no not_active Application Discontinuation
1999
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Publication number	Publication date
ES2100131A1 (es)	1997-06-01
NZ321607A (en)	2000-12-22
EA199700097A1 (ru)	1997-12-30
JPH10512457A (ja)	1998-12-02
HUP9801439A2 (hu)	1998-10-28
PT819764E (pt)	2002-09-30
AU702329B2 (en)	1999-02-18
CA2209927A1 (en)	1997-05-15
DE69619973T2 (de)	2002-11-07
JP2000106898A (ja)	2000-04-18
CZ252797A3 (cs)	1998-03-18
EP0819764A1 (en)	1998-01-21
US5994092A (en)	1999-11-30
CA2209927C (en)	2002-08-13
CN1177984A (zh)	1998-04-01
ES2176505T3 (es)	2002-12-01
CN1220779C (zh)	2005-09-28
NO973159D0 (no)	1997-07-08
ES2100131B1 (es)	1998-02-16
PL321257A1 (en)	1997-11-24
WO1997017464A1 (es)	1997-05-15
EA000684B1 (ru)	2000-02-28
SK100197A3 (en)	1998-02-04
AU7497796A (en)	1997-05-29
NO973159L (no)	1997-09-08
HUP9801439A3 (en)	2002-01-28
DE69619973D1 (de)	2002-04-25
KR19980701287A (ko)	1998-05-15
MX9705109A (es)	1998-06-30
BR9607092A (pt)	1997-11-11
ATE214740T1 (de)	2002-04-15
JP3036848B2 (ja)	2000-04-24

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